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Targeting the PI3K/AKT/mTOR Pathway in Cancer: Mechanisms and Therapeutic Inhibitors

The PI3K/AKT/mTOR signaling pathway exerts a pivotal regulatory role in the initiation and progression of diverse malignancies[1]. In the management of tumors, targeted inhibition of the PI3K/AKT/mTOR pathway has yielded substantial therapeutic advances, thereby paving the way for precision medicine strategies tailored to this signaling axis[1].
In this review, we systematically dissect the composition, role, and mechanism of the PI3K/AKT/mTOR pathway in cancer, and summarize the characteristics and applications of related inhibitors. It aims to provide researchers with a comprehensive and practical reference guide to support subsequent basic research and drug development.
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Overview of the PI3K/AKT/mTOR Pathway
Mechanisms of PI3K/AKT/mTOR in Cancer
PI3K/AKT/mTOR Inhibitors for Cancer Treatment
Overview of the PI3K/AKT/mTOR Pathway
Mechanisms of PI3K/AKT/mTOR in Cancer
PI3K/AKT/mTOR Inhibitors for Cancer Treatment
Overview of the PI3K/AKT/mTOR Pathway
The PI3K/AKT/mTOR signaling pathway constitutes a central intracellular signal transduction network. PI3Ks, classified as a family of membrane-associated lipid kinases, are directly activated by cell surface receptors, including receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Upon activation, PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3).
PIP3 then recruits AKT to the plasma membrane, where it undergoes full activation via phosphorylation mediated by both 3-phosphoinositide-dependent protein kinase 1 (PDK1) and mTOR complex 2 (mTORC2). Once activated, AKT regulates downstream effectors, including mTOR complex 1 (mTORC1) (Fig. 1)[1].
Figure 1. The PI3K/AKT/mTOR pathway under normal physiological conditions[1].
Dual Function of PI3K/AKT/mTOR in Cancer
The PI3K/AKT/mTOR axis modulates key metabolic processes, including glucose metabolism, macromolecular biosynthesis, and redox homeostasis maintenance[2]. It also regulates major cancer hallmarks, such as cell survival, metastasis, proliferation, metabolic reprogramming, and therapeutic resistance. Additionally, PI3K can influence the tumor microenvironment (TME)[3].
Dysregulation of this pathway drives cancer initiation and progression. For example, activating mutations in PIK3CA—encoding the p110α catalytic subunit of class IA PI3K—are detected in approximately 30%–40% of estrogen receptor-positive (ER+) breast cancers. These mutations enhance the kinase activity, promoting uncontrolled cell proliferation (Fig. 2)[1].
Notably, under certain physiological or pathological contexts, activation of the PI3K/AKT/mTOR pathway can elicit anti-tumor effects, highlighting its functional duality[3].
Figure 2. Aberrant activation of the PI3K/AKT/mTOR pathway leading to tumorigenesis and progression[1].
Mechanisms of PI3K/AKT/mTOR in Cancer
The PI3K/AKT/mTOR signaling pathway regulates tumor progression and chemoresistance by orchestrating multiple cellular processes, including epithelial-mesenchymal transition (EMT), apoptosis, autophagy, ferroptosis, glycolysis, and lipid metabolism. Among these processes, ferroptosis exerts robust anti-tumor effects, glycolysis represents a hallmark energy metabolic program that is uniquely in cancer cells, and autophagy can act as either a tumor promoter or suppressor. Apoptosis is also closely regulated by autophagy. This section focuses on ferroptosis, apoptosis, autophagy, and glycolysis to elucidate the pathway's complex regulatory mechanisms[3].
Mechanistic Role of PI3K/AKT/mTOR in Ferroptosis Regulation
Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation and oxidative membrane damage. Unlike apoptosis or necrosis, it is driven by metabolic perturbations associated with iron dyshomeostasis and reactive oxygen species (ROS) production. Induction of ferroptosis suppresses tumorigenesis[3].
The PI3K/AKT/mTOR pathway regulates ferroptosis, and its downregulation enhances ferroptosis in malignant cells, particularly those with PI3K mutations or PTEN deficiency, via suppression of GPX4, SREBP1, and SLC7A11 (Fig. 3)[3].
Figure 3. Regulation of apoptosis and ferroptosis by PI3K/AKT/mTOR[3].
Role of PI3K/AKT/mTOR in Autophagy and Tumor Adaptation
Autophagy maintains cellular homeostasis through degradation and recycling of damaged organelles and proteins. In the TME, the PI3K/AKT/mTOR axis is a key regulator of autophagy (Fig. 4); under hypoxia, it modulates angiogenesis and endothelial survival via the translation of hypoxia-inducible factor 1α (HIF-1α)[3].
Autophagy also contributes to chemoresistance, with PI3K/AKT/mTOR signaling influencing this process. For instance, UBE2S-mediated activation suppresses autophagic flux, promoting cisplatin resistance in ovarian cancer. In addition, although the PI3K/AKT pathway has been shown to accelerate tumorigenesis, activation of the PI3K/AKT/mTOR axis can inhibit autophagy in contexts where autophagy exerts a pro-tumorigenic (protective) role, consequently eliciting anti-tumor effects. Collectively, these findings underscore the reciprocal functional complexity of both autophagy and the PI3K/AKT/mTOR signaling axis[3].
Figure 4. PI3K/AKT-mediated modulation of autophagy[3].
PI3K/AKT/mTOR Regulation of Apoptosis
Apoptosis is a form of programmed cell death essential for maintaining cellular homeostasis by eliminating damaged, or senescent cells. It is characterized by cell shrinkage, chromatin condensation, plasma membrane blebbing, and the formation of apoptotic bodies that are engulfed by phagocytes. Dysregulated apoptosis is a hallmark of cancer, enabling uncontrolled cell proliferation.
The PI3K/AKT pathway is a critical regulator of apoptosis in malignancies (Fig. 3). Notably, inhibition of the PI3K/AKT/mTOR axis can suppress tumorigenesis and apoptotic resistance; however, it may simultaneously induce protective autophagy, which can paradoxically accelerate cancer progression[3].
Mechanisms Regulating Cancer Cell Metabolism
Glycolysis is a hallmark energy metabolic pathway in cancer cells. Elevated CPNE1 expression enhances aerobic glycolysis via the PI3K/AKT/HIF-1α signaling pathway, while PI3K inhibitors can abrogate this pro-glycolytic effect. These data highlight the central role of the PI3K/AKT pathway in regulating glycolytic metabolism in cancer[3].
PI3K/AKT/mTOR Inhibitors for Cancer Treatment
Targeting the PI3K/AKT/mTOR signaling pathway is a promising therapeutic strategy for cancer. Given the pathway's key role in tumor initiation and progression, inhibitors targeting this axis have attracted significant attention. For instance, Curcumin exerts anti-colorectal cancer effects and enhances ferroptosis by inhibiting the PI3K/AKT/mTOR pathway[3]. This section summarizes the characteristics and applications of different types of PI3K/AKT/mTOR inhibitors (Fig. 5).
Figure 5. PI3K/AKT/mTOR inhibitors[4].
PI3K Inhibitors[4-5]
The pan-PI3K inhibitors target all class IA PI3K isoforms (α, β, δ, and γ) (Fig. 6). Buparlisib (BKM120) is an orally bioavailable, reversible pan-class I PI3K inhibitor with activity against all four isoforms (α, β, γ, and δ) but not against class III PI3Ks or mTOR. Preclinical studies show robust antiproliferative effects in cancer cells with PIK3CA mutations.
• Isoform-specific PI3K Inhibitors
These selectively inhibit specific catalytic subunits. Alpelisib (BYL719), a PI3Kα-specific inhibitor, demonstrates favorable antitumor efficacy in xenograft models with PIK3CA alterations.
Akt Inhibitors[4]
Cancers with AKT1 mutations or AKT1/AKT2 amplification may be most sensitive to AKT inhibitors. However, these inhibitors do not block non-Akt PI3K effectors and may enhance PI3K-dependent activation of these effectors due to loss of negative feedback.
mTOR Inhibitors[4]
As a core component of the PI3K/AKT/mTOR axis, mTOR plays a pivotal role in mediating tumor progression and is a major drug target. mTOR inhibitors are generally classified into three main classes:
• Rapamycin and its analogs (rapalogs): selectively inhibit mTOR complex 1 (mTORC1).
• ATP-competitive mTOR inhibitors: target both mTORC1 and mTORC2.
• Dual PI3K/mTOR inhibitors: inhibit both PI3K and mTOR kinases.
Notably, rapamycin and rapalogs act by binding the intracellular receptor FK506-binding protein 12 (FKBP12). The resulting rapamycin-FKBP12 complex selectively binds mTORC1 but not mTORC2. This selective inhibition of mTORC1 can disrupt mTORC2-mediated negative feedback regulation of AKT, potentially promoting cancer cell survival and chemoresistance.
Figure 6. Pan‑PI3K inhibitors[5].
Summary
The PI3K/AKT/mTOR pathway regulates (promotes or inhibits) tumor progression and drug resistance through EMT, apoptosis, autophagy, ferroptosis, glycolysis, and lipid metabolism. Given its role in accelerating tumorigenesis, targeting this pathway with PI3K/AKT/mTOR inhibitors has shown strong potential for improving cancer outcomes. However, mTORC1-specific inhibitors may disrupt mTORC2-mediated feedback on AKT, potentially enhancing cancer cell survival and chemoresistance, underscoring the need for integrated strategies that precisely modulate this signaling axis for optimal therapeutic benefit.
Recommended Compounds and Screening Libraries
Category Product Name Cat. No. Description
Targeting the PI3K/AKT/mTOR Pathway
PI3K Inhibitors Buparlisib HY-70063 A pan-class I PI3K inhibitor.
Alpelisib HY-15244 A potent, selective, and orally active PI3Kα inhibitor.
Akt Inhibitors MK-2206 HY-108232 An orally active, highly potent and selective allosteric Akt inhibitor.
mTOR Inhibitors Torin 1 HY-13003 An inhibitor of both mTORC1 and mTORC2 complexes.
Everolimus HY-10218 A potent, selective and orally active mTOR1 inhibitor.
PDK1 Activator PS48 HY-15967 A PDK1 activator with an AC50 of 8 μM.
FKBP12 Degrader FKBP12 PROTAC RC32 HY-130835 A potent FKBP12 degrader based on PROTAC technology.
Modulating Modes of Cell Death
Ferroptosis Ferroptosis inducer-4 HY-161948 A ferroptosis inducer with terminal double bonds at the sn-2 position of phospholipids.
Autophagy and apoptosis Autophagy inducer 7 HY-171047 An autophagy and apoptosis inducer that activates autophagy by inhibiting Akt/mTOR signaling and downstream protein expression.
Apoptosis 2-Tetralone HY-30063 A apoptosis-inducing agent targeting MDM2 E3 ubiquitin kinase and the Bcl-w anti-apoptotic protein, exhibiting anticancer activity.
Apoptosis compound library HY-L003 Contains 3,149 apoptosis-related compounds focusing on key targets in the apoptosis signaling pathway, suitable for research on apoptosis and related diseases.